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1
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Schönberg J, Borlak J. miRNA biomarkers to predict risk of primary non-function of fatty allografts and drug induced acute liver failures. Mol Cell Biochem 2025; 480:2573-2593. [PMID: 39424772 PMCID: PMC11961548 DOI: 10.1007/s11010-024-05129-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/29/2024] [Indexed: 10/21/2024]
Abstract
Primary non-function (PNF) of an allograft defines an irreversible graft failure and although rare, constitutes a life-threatening condition that requires high-urgency re-transplantation. Equally, drug induced acute liver failures (ALF) are seldom but the rapid loss of hepatic function may require orthotropic liver transplantation (OLT). Recently, we reported the development of a rodent PNF-disease model of fatty allografts and showed that a dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of PNF. Based on findings from the rat PNF-disease model, we selected 15 miRNA-biomarker candidates for clinical validation and performed RT-qPCRs in well-documented PNF cases following OLT of fatty allografts. To assess specificity and selectivity, we compared their regulation in pre- and intraoperative liver biopsies and pre- and post-operative blood samples of patients undergoing elective hepatobiliary surgery. Additionally, we assessed their regulation in drug induced ALF. We confirmed clinical relevance for 11 PNF-associated miRNAs and found expression of miRNA-27b-3p, miRNA-122-3p, miRNA-125a-5p, miRNA-125b-5p and miRNA-192-5p to correlate with the hepatic steatosis grades. Furthermore, we demonstrate selectivity and specificity for the biomarker candidates with opposite regulation of let-7b-5p, miRNA-122-5p, miRNA-125b-5p and miRNA-194-5p in blood samples of patients following successful OLTs and/or liver resection. Moreover, by considering findings from 21 independent ALF-studies, we observed nine PNF-associated miRNAs regulated in common. We report miRNAs highly regulated in PNF and ALF, and their common regulation in different diseases broadens the perspective as biomarker candidates. Our study warrants independent confirmation in randomized clinical trials.
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Affiliation(s)
- Juliette Schönberg
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany.
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Li X, Feng J, Cheng H, Jin N, Jin S, Liu Z, Xu J, Xie J. Human umbilical cord mesenchymal stem cells enhance liver regeneration and decrease collagen content in fibrosis mice after partial hepatectomy by activating Wnt/β-catenin signaling. Acta Biochim Biophys Sin (Shanghai) 2024; 57:604-615. [PMID: 39716885 DOI: 10.3724/abbs.2024207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024] Open
Abstract
Liver fibrosis is a critical stage in the progression of various chronic liver diseases to cirrhosis and liver cancer. Early inhibition of liver fibrosis is crucial for the treatment of liver disease. Hepatectomy, a common treatment for liver-related diseases, promotes liver regeneration. However, in the context of liver fibrosis, liver regeneration is hindered. Many studies have shown that mesenchymal stem cells (MSCs) can promote liver regeneration after partial hepatectomy (PH). However, there are few reports on the impact of MSC therapy on liver regeneration post-PH in the context of hepatic fibrosis. The objective of this study is to examine the impact of MSCs on liver regeneration following PH in the fibrotic liver and uncover the related molecular mechanisms. This study reveals that MSC therapy significantly enhances liver function and mitigates liver inflammation after PH in the context of hepatic fibrosis. MSCs also significantly promote liver regeneration and alleviate liver fibrosis. In addition, this study identifies the role of MSCs in promoting liver regeneration and alleviating liver fibrosis via the activation of Wnt/β-catenin signaling. The combination of MSCs with hepatectomy may offer a novel approach for the treatment of liver fibrotic diseases.
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Affiliation(s)
- Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jinghui Feng
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Haiqin Cheng
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Ning Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Shanshan Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xu
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplant Center, the First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
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3
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El-Shanawany RM, El-Maadawy EA, El-Araby HA, Talaat RM. Impact of steroid therapy on pediatric acute liver failure: prognostic implication and interplay between TNF-α and miR-122. Mol Cell Pediatr 2024; 11:13. [PMID: 39666185 PMCID: PMC11638456 DOI: 10.1186/s40348-024-00185-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/05/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Acute liver failure (ALF) is a rare illness marked by rapid deterioration of liver function, leading to high morbidity and mortality rates, particularly in children. While steroids have been observed to correlate with improved survival, evidence supporting their efficacy in ALF children remains limited. miR-122, a liver-specific microRNA, plays a pivotal role in liver pathology, with its expression significantly altered in various liver diseases. Thus, it is considered a potential biomarker for disease progression, aids in prognosis, and identifies therapeutic targets. Our study aims to assess the expression of miR-122 in 24 children with ALF, both before and after steroid therapy, alongside its relationship with tumor necrosis factor-α (TNF-α), to better understand its potential role in treatment response and disease outcomes. miR-122 levels were determined using quantitative real-time RT-PCR (qRT-PCR), while TNF-α levels were assessed using enzyme-linked immunosorbent assay (ELISA) in patient sera. RESULTS In ALF children who survived after steroid treatment, miR-122 was markedly decreased compared to both pre-treatment levels (p = 0.003) and levels in deceased patients (p = 0.01). In addition, TNF-α levels significantly increased in surviving patients compared to pre-treatment levels (p = 0.008) and levels in deceased children (p = 0.028). A negative correlation was observed between TNF-α and miR-122 following steroids (r=-0.46, p = 0.04). miR-122 demonstrated 72% sensitivity and 67% specificity in distinguishing survivors and non-survivors, as indicated by its receiver-operated characteristic curve. A positive correlation was found between miR-122 before steroid therapy and both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) before (r = 0.641, p = 0.002 and r = 0.512, p = 0.02, respectively) and after (r = 0.492, p = 0.03 and r = 0.652, p = 0.003, respectively) steroids treatment. CONCLUSION Our data implies that lower miR-122 levels in steroids-treated ALF children are associated with a better outcome. Although miR-122 is not a strong standalone marker, it could be valuable in a biomarker panel. The increased TNF-α levels and decreased miR-122 expression indicate their involvement in the disease's pathophysiology. More studies are needed to validate our results.
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Affiliation(s)
- Rania M El-Shanawany
- Pediatric Hepatology, Gastroenterology, and Nutrition Department, National Liver Institute, Menoufia University, Menoufia, Shebin El-Koom, 32511, Egypt
| | - Eman A El-Maadawy
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Hanaa A El-Araby
- Pediatric Hepatology, Gastroenterology, and Nutrition Department, National Liver Institute, Menoufia University, Menoufia, Shebin El-Koom, 32511, Egypt
| | - Roba M Talaat
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt.
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McGill MR. The Role of Mechanistic Biomarkers in Understanding Acetaminophen Hepatotoxicity in Humans. Drug Metab Dispos 2024; 52:729-739. [PMID: 37918967 PMCID: PMC11257692 DOI: 10.1124/dmd.123.001281] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/18/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023] Open
Abstract
Our understanding of the fundamental molecular mechanisms of acetaminophen (APAP) hepatotoxicity began in 1973 to 1974, when investigators at the US National Institutes of Health published seminal studies demonstrating conversion of APAP to a reactive metabolite that depletes glutathione and binds to proteins in the liver in mice after overdose. Since then, additional groundbreaking experiments have demonstrated critical roles for mitochondrial damage, oxidative stress, nuclear DNA fragmentation, and necrotic cell death as well. Over the years, some investigators have also attempted to translate these mechanisms to humans using human specimens from APAP overdose patients. This review presents those studies and summarizes what we have learned about APAP hepatotoxicity in humans so far. Overall, the mechanisms of APAP hepatotoxicity in humans strongly resemble those discovered in experimental mouse and cultured hepatocyte models, and emerging biomarkers also suggest similarities in liver repair. The data not only validate the first mechanistic studies of APAP-induced liver injury performed 50 years ago but also demonstrate the human relevance of numerous studies conducted since then. SIGNIFICANCE STATEMENT: Human studies using novel translational, mechanistic biomarkers have confirmed that the fundamental mechanisms of acetaminophen (APAP) hepatotoxicity discovered in rodent models since 1973 are the same in humans. Importantly, these findings have guided the development and understanding of treatments such as N-acetyl-l-cysteine and 4-methylpyrazole over the years. Additional research may improve not only our understanding of APAP overdose pathophysiology in humans but also our ability to predict and treat serious liver injury in patients.
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Affiliation(s)
- Mitchell R McGill
- Department of Environmental Health Sciences, Fay W. Boozman College of Public Health; Department of Pharmacology and Toxicology, College of Medicine; and Department of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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5
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Koch PF, Ludwig K, Krenzien F, Hillebrandt KH, Schöning W, Pratschke J, Raschzok N, Sauer IM, Moosburner S. miRNA as potential biomarkers after liver transplantation: A systematic review. Transplant Rev (Orlando) 2024; 38:100831. [PMID: 38237243 DOI: 10.1016/j.trre.2024.100831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/12/2023] [Accepted: 01/08/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Liver transplantation is a life-saving therapy for end-stage liver disease patients, but acute cellular rejection (ACR) and graft complications remain significant postoperative challenges. Early and accurate diagnosis is crucial for timely intervention and improved patient outcomes, but their diagnosis rely currently on invasive biopsy sampling, thus prompting the search for non-invasive Biomarkers. MicroRNA (miRNA) have emerged as promising biomarkers in various pathological conditions, and their potential utility in diagnosing acute cellular rejection after liver transplantation has gained significant interest. METHODS This systematic review of PubMed, Web of Science, and the ClinicalTrials.gov registry analyzes studies exploring miRNA as biomarkers for ACR and graft dysfunction in liver transplantation (PROSPERO ID CRD42023465278). The Cochrane Collaboration tool for assessing risk of bias was employed. Population data, identified miRNA and their dynamic regulation, as well as event prediction were compared. Data extraction and quality assessment were performed independently by two reviewers. RESULTS Thirteen studies were included in this systematic review. Various investigated miRNAs were upregulated in association with acute cellular rejection, like miR-122, miR-155, miR-181, miR-483-3p, and miR-885-5p, demonstrating great biomarker potential. Additionally, several studies conducted target gene analysis, revealing insights into cellular mechanisms linked to ACR. Moreover, various miRNA were also capable of predicting different organ complications following transplantation, expanding their versatility. Remaining challenges include the standardization of miRNA profiling, the need for functional validation, and the necessity for long-term studies. CONCLUSION The results highlight the potential of miRNA as specific, non-invasive biomarkers for ACR and graft dysfunction following liver transplantation. However, further research is needed to validate these findings and establish standardized diagnostic panels to incorporate them into clinical practice and explore miRNA-based therapies in the future.
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Affiliation(s)
- Pia F Koch
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany
| | - Kristina Ludwig
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany; BIH Charité Clinician Scientist Program, BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Karl H Hillebrandt
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany; BIH Charité Clinician Scientist Program, BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Wenzel Schöning
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany
| | - Nathanael Raschzok
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany; BIH Charité Clinician Scientist Program, BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
| | - Igor M Sauer
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany.
| | - Simon Moosburner
- Department of Surgery, Experimental Surgery, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité - Universitätsmedizin Berlin, Campus Charité Mitte/Campus Virchow-Klinikum, Berlin, Germany; BIH Charité Clinician Scientist Program, BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
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6
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential of microRNA-based therapy for patients with liver failure syndromes and hepatocellular carcinoma. Expert Opin Ther Targets 2024; 28:179-191. [PMID: 38487923 DOI: 10.1080/14728222.2024.2331598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
INTRODUCTION Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation. AREAS COVERED We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials. EXPERT OPINION microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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Xu C, Yan F, Zhao Y, Jaeschke H, Wu J, Fang L, Zhao L, Zhao Y, Wang L. Hepatocyte miR-21-5p-deficiency alleviates APAP-induced liver injury by inducing PPARγ and autophagy. Toxicol Sci 2024; 198:50-60. [PMID: 38180883 PMCID: PMC11491925 DOI: 10.1093/toxsci/kfad132] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2024] Open
Abstract
Acetaminophen (APAP)-induced liver injury is one of the most frequent causes of acute liver failure worldwide. Significant increases in the levels of miRNA-21 in both liver tissues and plasma have been observed in APAP-overdosed animals and humans. However, the mechanistic effect of miRNA-21 on acute liver injury remains unknown. In this study, we generated a new hepatocyte-specific miRNA-21 knockout (miR-21-HKO) mouse line. miR-21-HKO and the background-matched sibling wild-type (WT) mice were treated with a toxic dose of APAP. Compared with WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3 beta, which suggested an autophagy activation. The expression of PPARγ was highly induced in the livers of miR-21-HKO mice after a 2-h APAP treatment, which preceded the activation of LC3B at the 12 h APAP treatment. miR-21 negatively regulated PPARγ protein expression by targeting its 3'-UTR. When PPARγ function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPARγ signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPARγ and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury.
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Affiliation(s)
- Chao Xu
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
| | - Fang Yan
- Department of Pain Management, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yulan Zhao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
| | - Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA
| | - Li Fang
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
| | - Lifang Zhao
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China
| | - Yuanfei Zhao
- Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing, 100029, China
| | - Li Wang
- Independent Researcher, Tucson, Arizona 85004, USA
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential in developing microRNA associated with regeneration as biomarkers to improve prognostication for liver failure syndromes and hepatocellular carcinoma. Expert Rev Mol Diagn 2024; 24:5-22. [PMID: 38059597 DOI: 10.1080/14737159.2023.2292642] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/05/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Determining the need for liver transplantation remains critical in the management of hepatocellular carcinoma (HCC) and liver failure syndromes (including acute liver failure and decompensated cirrhosis states). Conventional prognostic models utilize biomarkers of liver and non-liver failure and have limitations in their application. Novel biomarkers which predict regeneration may fulfil this niche. microRNA are implicated in health and disease and are present in abundance in the circulation. Despite this, they have not translated into mainstream clinical biomarkers. AREAS COVERED We will discuss current challenges in the prognostication of patients with liver failure syndromes as well as for patients with HCC. We will discuss biomarkers implicated with liver regeneration. We then provide an overview of the challenges in developing microRNA into clinically tractable biomarkers. Finally, we will provide a scoping review of microRNA which may have potential as prognostic biomarkers in liver failure syndromes and HCC. EXPERT OPINION Novel biomarkers are needed to improve prognostic models in liver failure syndromes and HCC. Biomarkers associated with liver regeneration are currently lacking and may fulfil this niche. microRNA have the potential to be developed into clinically tractable biomarkers but a consensus on standardizing methodology and reporting is required prior to large-scale studies.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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McGill MR, Curry SC. The Evolution of Circulating Biomarkers for Use in Acetaminophen/Paracetamol-Induced Liver Injury in Humans: A Scoping Review. LIVERS 2023; 3:569-596. [PMID: 38434489 PMCID: PMC10906739 DOI: 10.3390/livers3040039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/05/2024] Open
Abstract
Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers of liver injury as opposed to liver function. Thus, the field of liver injury biomarkers has evolved alongside the growth in APAP hepatotoxicity incidence. Numerous biomarkers have been proposed for use in the management of APAP overdose patients in the intervening years. Here, we comprehensively review the development of these markers from the 1960s to the present day and briefly discuss possible future directions.
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Affiliation(s)
- Mitchell R McGill
- Dept. of Environmental Health Sciences, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
- Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
- Dept. of Pathology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212, USA
| | - Steven C Curry
- Division of Clinical Data Analytics and Decision Support, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85006, USA
- Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ 85006, USA
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10
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Shao JL, Wang LJ, Xiao J, Yang JF. Non-coding RNAs: The potential biomarker or therapeutic target in hepatic ischemia-reperfusion injury. World J Gastroenterol 2023; 29:4927-4941. [PMID: 37731999 PMCID: PMC10507504 DOI: 10.3748/wjg.v29.i33.4927] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/22/2023] [Accepted: 08/18/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) is the major complication of liver surgery and liver transplantation, that may increase the postoperative morbidity, mortality, tumor progression, and metastasis. The underlying mechanisms have been extensively investigated in recent years. Among these, oxidative stress, inflammatory responses, immunoreactions, and cell death are the most studied. Non-coding RNAs (ncRNAs) are defined as the RNAs that do not encode proteins, but can regulate gene expressions. In recent years, ncRNAs have emerged as research hotspots for various diseases. During the progression of HIRI, ncRNAs are differentially expressed, while these dysregulations of ncRNAs, in turn, have been verified to be related to the above pathological processes involved in HIRI. ncRNAs mainly contain microRNAs, long ncRNAs, and circular RNAs, some of which have been reported as biomarkers for early diagnosis or assessment of liver damage severity, and as therapeutic targets to attenuate HIRI. Here, we briefly summarize the common pathophysiology of HIRI, describe the current knowledge of ncRNAs involved in HIRI in animal and human studies, and discuss the potential of ncRNA-targeted therapeutic strategies. Given the scarcity of clinical trials, there is still a long way to go from pre-clinical to clinical application, and further studies are needed to uncover their potential as therapeutic targets.
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Affiliation(s)
- Jia-Li Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Li-Juan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Ji Xiao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
| | - Jin-Feng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan Province, China
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Qing Y, Fang H, Yang Y, Liao Y, Li H, Wang Z, Du J. Enzyme-Assisted Amplification and Copper Nanocluster Fluorescence Signal-Based Method for miRNA-122 Detection. BIOSENSORS 2023; 13:854. [PMID: 37754088 PMCID: PMC10526218 DOI: 10.3390/bios13090854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/15/2023] [Accepted: 08/26/2023] [Indexed: 09/28/2023]
Abstract
At present, a large number of studies have demonstrated that miRNAs can be used as biological indicators for the diagnosis and treatment of diseases such as tumours and cancer, so it is important to develop a new miRNA detection platform. In this work, miRNA-122 is used as the basis for targeting detection agents. We have designed an unlabelled DNA1 that undergoes partial hybridisation and has a 20 T base long strand. The fluorescent signal in this experiment is derived from copper nanoclusters (CuNCs) generated on the circular T-long strand of DNA1. At the same time, DNA1 is able to react with miRNA-122 and achieve hydrolysis of the part bound to miRNA-122 via the action of nucleic acid exonuclease III (Exo III), leaving a part of the DNA, called DNA3, while releasing miRNA-122 to participate in the next reaction, thus achieving circular amplification. DNA3 is able to react with DNA2, which is bound to streptavidin magnetic beads (SIBs) and separated from the reaction solution via the application of a magnetic field. Overall, this is a fluorescence signal reduction experiment, and the strength of the fluorescence signal from the copper nanoclusters can determine whether the target miRNA-122 is present or not. The degree of fluorescence reduction indicates how much DNA1, and thus the amount of target miRNA-122, has been hydrolysed. By evaluating the variations in the fluorescence signal under optimised conditions, we discovered that this method has good sensitivity, with a detection limit as low as 0.46 nM, better than many other previous works on fluorescence signal-based biosensors for miRNA detection. This technique offers high discrimination and selectivity and can serve as a persuasive reference for early diagnosis.
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Affiliation(s)
| | | | | | | | | | | | - Jie Du
- State Key Laboratory of Marine Resource Utilization in South China Sea, College of Materials Science and Engineering, Hainan University, Haikou 570228, China; (Y.Q.); (H.F.); (Y.Y.); (Y.L.); (H.L.); (Z.W.)
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12
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Blake MJ, Steer CJ. Liver Regeneration in Acute on Chronic Liver Failure. Clin Liver Dis 2023; 27:595-616. [PMID: 37380285 DOI: 10.1016/j.cld.2023.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Liver regeneration is a multifaceted process by which the organ regains its original size and histologic organization. In recent decades, substantial advances have been made in our understanding of the mechanisms underlying regeneration following loss of hepatic mass. Liver regeneration in acute liver failure possesses several classic pathways, while also exhibiting unique differences in key processes such as the roles of differentiated cells and stem cell analogs. Here we summarize these unique differences and new molecular mechanisms involving the gut-liver axis, immunomodulation, and microRNAs with an emphasis on applications to the patient population through stem cell therapies and prognostication.
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Affiliation(s)
- Madelyn J Blake
- Department of Medicine, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 36, Minneapolis, MN 55455, USA.
| | - Clifford J Steer
- Department of Medicine, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 36, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, 420 Delaware Street Southeast, MMC 36, Minneapolis, MN 55455, USA
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13
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Huffman AM, Syed M, Rezq S, Anderson CD, Yanes Cardozo LL, Romero DG. Loss of microRNA-21 protects against acetaminophen-induced hepatotoxicity in mice. Arch Toxicol 2023; 97:1907-1925. [PMID: 37179516 PMCID: PMC10919897 DOI: 10.1007/s00204-023-03499-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 04/17/2023] [Indexed: 05/15/2023]
Abstract
Acetaminophen (APAP)-induced Acute Liver Failure (ALF) is recognized as the most common cause of ALF in Western societies. APAP-induced ALF is characterized by coagulopathy, hepatic encephalopathy, multi-organ failure, and death. MicroRNAs are small, non-coding RNAs that regulate gene expression at the post-transcriptional level. MicroRNA-21 (miR-21) is dynamically expressed in the liver and is involved in the pathophysiology of both acute and chronic liver injury models. We hypothesize that miR-21genetic ablation attenuates hepatotoxicity following acetaminophen intoxication. Eight-week old miR-21knockout (miR21KO) or wild-type (WT) C57BL/6N male mice were injected with acetaminophen (APAP, 300 mg/kg BW) or saline. Mice were sacrificed 6 or 24 h post-injection. MiR21KO mice presented attenuation of liver enzymes ALT, AST, LDH compared with WT mice 24 h post-APAP treatment. Moreover, miR21KO mice had decreased hepatic DNA fragmentation and necrosis than WT mice after 24 h of APAP treatment. APAP-treated miR21KO mice showed increased levels of cell cycle regulators CYCLIN D1 and PCNA, increased autophagy markers expression (Map1LC3a, Sqstm1) and protein (LC3AB II/I, p62), and an attenuation of the APAP-induced hypofibrinolytic state via (PAI-1) compared with WT mice 24 post-APAP treatment. MiR-21 inhibition could be a novel therapeutic approach to mitigate APAP-induced hepatotoxicity and enhance survival during the regenerative phase, particularly to alter regeneration, autophagy, and fibrinolysis. Specifically, miR-21 inhibition could be particularly useful when APAP intoxication is detected at its late stages and the only available therapy is minimally effective.
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Affiliation(s)
- Alexandra M Huffman
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
- Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
| | - Maryam Syed
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Samar Rezq
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Christopher D Anderson
- Department of Surgery, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Licy L Yanes Cardozo
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA
| | - Damian G Romero
- Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS, 39216, USA.
- Mississippi Center of Excellence in Perinatal Research, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
- Women's Health Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
- Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
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14
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Sani F, Sani M, Moayedfard Z, Darayee M, Tayebi L, Azarpira N. Potential advantages of genetically modified mesenchymal stem cells in the treatment of acute and chronic liver diseases. Stem Cell Res Ther 2023; 14:138. [PMID: 37226279 DOI: 10.1186/s13287-023-03364-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 05/04/2023] [Indexed: 05/26/2023] Open
Abstract
Liver damage caused by toxicity can lead to various severe conditions, such as acute liver failure (ALF), fibrogenesis, and cirrhosis. Among these, liver cirrhosis (LC) is recognized as the leading cause of liver-related deaths globally. Unfortunately, patients with progressive cirrhosis are often on a waiting list, with limited donor organs, postoperative complications, immune system side effects, and high financial costs being some of the factors restricting transplantation. Although the liver has some capacity for self-renewal due to the presence of stem cells, it is usually insufficient to prevent the progression of LC and ALF. One potential therapeutic approach to improving liver function is the transplantation of gene-engineered stem cells. Several types of mesenchymal stem cells from various sources have been suggested for stem cell therapy for liver disease. Genetic engineering is an effective strategy that enhances the regenerative potential of stem cells by releasing growth factors and cytokines. In this review, we primarily focus on the genetic engineering of stem cells to improve their ability to treat damaged liver function. We also recommend further research into accurate treatment methods that involve safe gene modification and long-term follow-up of patients to increase the effectiveness and reliability of these therapeutic strategies.
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Affiliation(s)
- Farnaz Sani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mahsa Sani
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Darayee
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, P.O. Box: 7193711351, Shiraz, Iran.
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15
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Ma J, Xu Y, Zhang M, Li Y. Geraniol ameliorates acute liver failure induced by lipopolysaccharide/D-galactosamine via regulating macrophage polarization and NLRP3 inflammasome activation by PPAR-γ methylation Geraniol alleviates acute liver failure. Biochem Pharmacol 2023; 210:115467. [PMID: 36849063 DOI: 10.1016/j.bcp.2023.115467] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/18/2023] [Accepted: 02/21/2023] [Indexed: 03/01/2023]
Abstract
Geraniol (Ger), a natural acyclic monoterpene alcohol, has been reported to exert protective effects through anti-inflammation in Acute liver failure (ALF). However, its specific roles and precise mechanisms underlying anti-inflammatory effects in ALF have not yet fully explored. We aimed to investigated the hepatoprotective effects and mechanisms of Ger against ALF induced by lipopolysaccharide (LPS)/D-galactosamine (GaIN). In this study, the liver tissue and serum of LPS/D-GaIN-induced mice were collected. The degree of liver tissue injury was evaluated by HE and TUNEL staining. Serum levels of liver injury markers (ALT and AST) and inflammatory factors were measured by ELISA assays. PCR and western blotting were conducted to determine the expression of inflammatory cytokines, NLRP3 inflammasome-related proteins, PPAR-γ pathway-related proteins, DNA Methyltransferases and M1/M2 polarization cytokines. Immunofluorescence staining was used to assess the localization and expression of macrophage markers (F4/80 and CD86), NLRP3 and PPAR-γ. In vitro experiments were performed in macrophages stimulated with LPS with or without IFN-γ. Purification of macrophages and cell apoptosis was analyzed using flow cytometry. We found that Ger effectively alleviated ALF in mice, specified by the attenuation of liver tissue pathological damage, inhibition of ALT, AST and inflammatory factor levels, and inactivation of NLRP3 inflammasome. Meanwhile, downregulation M1 macrophage polarization may involve in the protective effects of Ger. In vitro, Ger reduced the activation of NLRP3 inflammasome and apoptosis through regulating PPAR-γ methylation by inhibiting M1 macrophage polarization. In conclusion, Ger protects against ALF through suppressing NLRP3 inflammasome-mediated inflammation and LPS-induced macrophage M1 polarization via modulating PPAR-γ methylation.
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Affiliation(s)
- Jing Ma
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China
| | - Yun Xu
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China
| | - Min Zhang
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China
| | - Yi Li
- Infectious Disease Department, The Second XIANGYA Hospital of Central South University, Changsha, Hunan, China.
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16
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Doghish AS, Elballal MS, Elazazy O, Elesawy AE, Elrebehy MA, Shahin RK, Midan HM, Sallam AAM. The role of miRNAs in liver diseases: Potential therapeutic and clinical applications. Pathol Res Pract 2023; 243:154375. [PMID: 36801506 DOI: 10.1016/j.prp.2023.154375] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/10/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023]
Abstract
MicroRNAs (miRNAs) are a class of short, non-coding RNAs that function post-transcriptionally to regulate gene expression by binding to particular mRNA targets and causing destruction of the mRNA or translational inhibition of the mRNA. The miRNAs control the range of liver activities, from the healthy to the unhealthy. Considering that miRNA dysregulation is linked to liver damage, fibrosis, and tumorigenesis, miRNAs are a promising therapeutic strategy for the evaluation and treatment of liver illnesses. Recent findings on the regulation and function of miRNAs in liver diseases are discussed, with an emphasis on miRNAs that are highly expressed or enriched in hepatocytes. Alcohol-related liver illness, acute liver toxicity, viral hepatitis, hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and exosomes in chronic liver disease all emphasize the roles and target genes of these miRNAs. We briefly discuss the function of miRNAs in the etiology of liver diseases, namely in the transfer of information between hepatocytes and other cell types via extracellular vesicles. Here we offer some background on the use of miRNAs as biomarkers for the early prognosis, diagnosis, and assessment of liver diseases. The identification of biomarkers and therapeutic targets for liver disorders will be made possible by future research into miRNAs in the liver, which will also help us better understand the pathogeneses of liver diseases.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
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17
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Feng Z, Bao S, Kong L, Chen X. MicroRNA-378 inhibits hepatocyte apoptosis during acute liver failure by targeting caspase-9 in mice. GASTROENTEROLOGIA Y HEPATOLOGIA 2023; 46:124-134. [PMID: 35964807 DOI: 10.1016/j.gastrohep.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 06/18/2022] [Accepted: 07/16/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. It has been demonstrated that micro ribonucleic acids (miRNAs) are crucial mediators of nearly all pathological processes, including liver disease. OBJECTIVE The present study investigates the role of miR-378 in ALF. An ALF mouse model was induced using intraperitoneal injections of d-galactosamine/lipopolysaccharide (d-GalN/LPS). A hepatocyte cell line and miR-378 analogue were used in vitro to investigate the possible roles of miR-378 in ALF. METHODS The expressions of miR-378 and predicted target genes were measured via reverse transcription-quantitative polymerase chain reaction and western blotting, and cell apoptosis was assayed using flow cytometry. RESULTS Compared with mice in the control group, the mice challenged with d-GalN/LPS showed higher levels of alanine aminotransferase, aspartate aminotransferase, tumour necrosis factor-alpha and interleukin-6, more severe liver damage and increased numbers of apoptotic hepatocytes. Hepatic miR-378 was distinctly downregulated, while messenger RNA and protein levels of cysteinyl aspartate specific proteinase 9 (caspase-9) were upregulated in the ALF model. Furthermore, miR-378 was downregulated in d-GalN/TNF-induced hepatocyte cells, and miR-378 was found to inhibit hepatocyte apoptosis by targeting caspase-9. CONCLUSION Together, the present results indicate that miR-378 is a previously unrecognised post-ALF hepatocyte apoptosis regulator and may be a potential therapeutic target in the context of ALF.
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Affiliation(s)
- Zhiwen Feng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
| | - Shenghua Bao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
| | - Lianbao Kong
- Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaopeng Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
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18
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Orzeł-Gajowik K, Milewski K, Zielińska M. Insight into microRNAs-Mediated Communication between Liver and Brain: A Possible Approach for Understanding Acute Liver Failure? Int J Mol Sci 2021; 23:224. [PMID: 35008650 PMCID: PMC8745738 DOI: 10.3390/ijms23010224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 01/11/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening consequence of hepatic function rapid loss without preexisting liver disease. ALF may result in a spectrum of neuropsychiatric symptoms that encompasses cognitive impairment, coma, and often death, collectively defined as acute hepatic encephalopathy. Micro RNAs are small non-coding RNAs that modulate gene expression and are extensively verified as biomarker candidates in various diseases. Our systematic literature review based on the last decade's reports involving a total of 852 ALF patients, determined 205 altered circulating miRNAs, of which 25 miRNAs were altered in the blood, regardless of study design and methodology. Selected 25 miRNAs, emerging predominantly from the analyses of samples obtained from acetaminophen overdosed patients, represent the most promising biomarker candidates for a diagnostic panel for symptomatic ALF. We discussed the role of selected miRNAs in the context of tissue-specific origin and its possible regulatory role for molecular pathways involved in blood-brain barrier function. The defined several common pathways for 15 differently altered miRNAs were relevant to cellular community processes, indicating loss of intercellular, structural, and functional components, which may result in blood-brain barrier impairment and brain dysfunction. However, a causational relationship between circulating miRNAs differential expression, and particular clinical features of ALF, has to be demonstrated in a further study.
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Affiliation(s)
| | | | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland; (K.O.-G.); (K.M.)
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19
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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20
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Sasidharan V, Sánchez Alvarado A. The Diverse Manifestations of Regeneration and Why We Need to Study Them. Cold Spring Harb Perspect Biol 2021; 14:a040931. [PMID: 34750171 PMCID: PMC9438785 DOI: 10.1101/cshperspect.a040931] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
For hundreds of years, the question of why some organisms can regenerate missing body parts while others cannot has remained poorly understood. This has been due in great part to the inability to genetically, molecularly, and cellularly dissect this problem for most of the history of the field. It has only been in the past 20-30 years that important mechanistic advances have been made in methodologies that introduce loss and gain of gene function in animals that can regenerate. However, we still have a very incomplete understanding of how broadly regenerative abilities may be dispersed across species and whether or not such properties share a common evolutionary origin, which may have emerged independently or both. Understanding regeneration, therefore, will require rigorously practiced fundamental, curiosity-driven, discovery research. Expanding the number of research organisms used to study regeneration allows us to uncover aspects of this problem we may not yet know exist and simultaneously increases our chances of solving this long-standing problem of biology.
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21
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Tavabie OD, Karvellas CJ, Salehi S, Speiser JL, Rose CF, Menon K, Prachalias A, Heneghan MA, Agarwal K, Lee WM, McPhail MJW, Aluvihare VR. A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure. J Hepatol 2021; 75:424-434. [PMID: 33857547 PMCID: PMC10668489 DOI: 10.1016/j.jhep.2021.03.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 02/26/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. METHODS We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. RESULTS Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. CONCLUSIONS Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. LAY SUMMARY While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.
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Affiliation(s)
| | - Constantine J Karvellas
- Division of Gastroenterology and Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Jaime L Speiser
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, North Carolina, USA
| | - Christopher F Rose
- Hepato-neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Krishna Menon
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Texas, USA
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Busche S, John K, Wandrer F, Vondran FWR, Lehmann U, Wedemeyer H, Essmann F, Schulze-Osthoff K, Bantel H. BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment. Cell Death Dis 2021; 12:736. [PMID: 34312366 PMCID: PMC8313681 DOI: 10.1038/s41419-021-04020-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.
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Affiliation(s)
- Stephanie Busche
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katharina John
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Franziska Wandrer
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Florian W. R. Vondran
- grid.10423.340000 0000 9529 9877Department of Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany ,grid.452463.2German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Hannover, Germany
| | - Ulrich Lehmann
- grid.10423.340000 0000 9529 9877Department of Pathology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Frank Essmann
- grid.502798.10000 0004 0561 903XDr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
| | - Klaus Schulze-Osthoff
- grid.10392.390000 0001 2190 1447Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany ,grid.7497.d0000 0004 0492 0584German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.10392.390000 0001 2190 1447Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen, Germany
| | - Heike Bantel
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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De Clercq P, Geerts A, Van Vlierberghe H, Verhelst X. The utility of biomarkers in prognosis assessment of patients with acute liver failure. Hepatol Res 2021; 51:750-757. [PMID: 34076937 DOI: 10.1111/hepr.13668] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 04/16/2021] [Accepted: 05/07/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Acute liver failure (ALF) is a rare but potential lethal condition characterized by the sudden development of jaundice, coagulopathy and hepatic encephalopathy in patients without underlying liver disease. In selected patients, emergency liver transplantation is required. Selection of these patients is based on clinical criteria such as the Kings College Criteria (KCC) or the Clichy criteria. AIMS The aim of this work is to provide an overview of potential biomarkers that could improve the prognostic value of KCC. RESULTS Several promising biomarkers involved in related pathophysiological processes have been identified. Some could be as stand-alone biomarkers; however, the best prognostic values have been observed in the combination of biomarkers with current models. Among these, the ALFSG Index that combines clinical parameters and circulating blood levels of CK18 claims a higher prognostic value than KCC. CONCLUSIONS In this review, all potential biomarkers for ALF have been summarized to give an overview of the work performed over the last years, and a glimpse of what to expect in this field in the coming years.
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Affiliation(s)
- Pauline De Clercq
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium
| | - Anja Geerts
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium.,Ghent Liver Research Center, Ghent University, Gent, Belgium
| | - Hans Van Vlierberghe
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium.,Ghent Liver Research Center, Ghent University, Gent, Belgium
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Gent, Belgium.,Ghent Liver Research Center, Ghent University, Gent, Belgium
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24
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Abstract
Genomic and transcriptomic analyses have well established that the major fraction of the mammalian genome is transcribed into different classes of RNAs ranging in size from a few nucleotides to hundreds of thousands of nucleotides, which do not encode any protein. Some of these noncoding RNAs (ncRNAs) are directly or indirectly linked to the regulation of expression or functions of 25,000 proteins coded by <2% of the human genome. Among these regulatory RNAs, microRNAs are small (2125 nucleotides) RNAs that are processed from precursor RNAs that have stemloop structure, whereas noncoding RNAs >200 nucleotides are termed long noncoding RNAs (lncRNAs). Circular RNAs (circRNAs) are newly identified lncRNA members that are generated by back-splicing of primary transcripts. The functions of ncRNAs in modulating liver toxicity of xenobiotics are emerging only recently. Acetaminophen (N-acetyl-para-aminophenol, paracetamol or APAP) is a safe analgesic and antipyretic drug at the therapeutic dose. However, it can cause severe liver toxicity that may lead to liver failure if overdosed or combined with alcohol, herbs, or other xenobiotics. This review discusses the role of ncRNAs in acetaminophen metabolism, toxicity, and liver regeneration after APAP-induced liver injury (AILI).
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Affiliation(s)
- Vivek Chowdhary
- *Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA
- †Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Pipasha Biswas
- †Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Kalpana Ghoshal
- *Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH, USA
- †Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, USA
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25
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Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2021; 70:784-795. [PMID: 33127832 DOI: 10.1136/gutjnl-2020-322526] [Citation(s) in RCA: 277] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.
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Affiliation(s)
- Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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26
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Matthews O, Morrison EE, Tranter JD, Starkey Lewis P, Toor IS, Srivastava A, Sargeant R, Rollison H, Matchett KP, Kendall TJ, Gray GA, Goldring C, Park K, Denby L, Dhaun N, Bailey MA, Henderson NC, Williams D, Dear JW. Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells. EBioMedicine 2020; 62:103092. [PMID: 33232872 PMCID: PMC7689533 DOI: 10.1016/j.ebiom.2020.103092] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney. METHODS Dicerflox/flox mice were treated with a Cre recombinase-expressing adenovirus (AAV8) to selectively inhibit hepatocyte microRNA production (Dicer-CKO). Organ microRNA expression was measured in health and following paracetamol toxicity. The functional consequence of hepatic microRNA transfer was determined by measuring the expression and activity of cytochrome P450 2E1 (target of the hepatocellular miR-122), and by measuring the effect of serum extracellular vesicles (ECVs) on proximal tubular cell injury. In humans with liver injury we measured microRNA expression in urinary ECVs. A murine model of myocardial infarction was used as a non-hepatic model of microRNA release. FINDINGS Dicer-CKO mice demonstrated a decrease in kidney miR-122 in the absence of other microRNA changes. During hepatotoxicity, miR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Depletion of hepatocyte microRNA increased kidney cytochrome P450 2E1 expression and activity. Serum ECVs from mice with hepatotoxicity increased proximal tubular cell miR-122 and prevented cisplatin toxicity. miR-122 increased in urinary ECVs during human hepatotoxicity. Transfer of microRNA was not restricted to liver injury -miR-499 was released following cardiac injury and correlated with an increase in the kidney. INTERPRETATION Physiological transfer of functional microRNA to the kidney is increased by liver injury and this signalling represents a new paradigm for understanding the relationship between liver injury and renal function. FUNDING Kidney Research UK, Medical Research Scotland, Medical Research Council.
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Affiliation(s)
- Olivia Matthews
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Emma E Morrison
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - John D Tranter
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Philip Starkey Lewis
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, United Kingdom
| | - Iqbal S Toor
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Abhishek Srivastava
- AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
| | - Rebecca Sargeant
- AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
| | - Helen Rollison
- AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
| | - Kylie P Matchett
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Timothy J Kendall
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Gillian A Gray
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Chris Goldring
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom
| | - Kevin Park
- Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom
| | - Laura Denby
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Neeraj Dhaun
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Matthew A Bailey
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom
| | - Neil C Henderson
- Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, United Kingdom
| | - Dominic Williams
- AstraZeneca, Clinical Pharmacology & Safety Sciences Department, Biopharmaceuticals Science Unit, Darwin Building 310, Cambridge Science Park, Milton Rd, Cambridge, CB4 0FZ. United Kingdom
| | - James W Dear
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom.
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27
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Yang JQ, Jiang N, Li ZP, Guo S, Chen ZY, Li BB, Chai SB, Lu SY, Yan HF, Sun PM, Zhang T, Sun HW, Yang JW, Zhou JL, Yang HM, Cui Y. The effects of microgravity on the digestive system and the new insights it brings to the life sciences. LIFE SCIENCES IN SPACE RESEARCH 2020; 27:74-82. [PMID: 34756233 DOI: 10.1016/j.lssr.2020.07.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/04/2020] [Accepted: 07/28/2020] [Indexed: 06/13/2023]
Abstract
BACKGROUND Weightlessness is a component of the complex space environment. It exerts adverse effects on the human body, and may pose unknown challenges to the implementation of space missions. The regular function of the digestive system is an important checkpoint for astronauts to conduct missions. Simulated microgravity can recreate the changes experienced by the human body in a weightless environment in space to a certain extent, providing technical support for the exploration of its mechanism and a practical method for other scientific research. METHODS AND MATERIALS In the present study, we reviewed and discussed the latest research on the effects of weightlessness or simulated microgravity on the digestive system, as well as the current challenges and future expectations for progress in medical science and further space exploration. RESULTS A series of studies have investigated the effects of weightlessness on the human digestive system. On one hand, weightlessness and the changing space environment may exert certain adverse effects on the human body. Studies based on cells or animals have demonstrated the complex effects on the human digestive system in response to weightlessness. On the other hand, a microgravity environment also facilitates the ideation of novel concepts for research in the domain of life science. CONCLUSION The effects of weightlessness on the digestive system are considerably complicated. The emergence of methods that help simulate a weightless environment provides a more convenient alternative for assessing the impact and the mechanism underlying the effect of weightlessness on the human body. In addition, the simulated microgravity environment facilitates the ideation of novel concepts for application in regenerative medicine and other fields of life science.
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Affiliation(s)
- Jia-Qi Yang
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China; Department of General Surgery, the 306th Hospital of Chinese PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Nan Jiang
- The Center for Hepatopancreatobiliary Diseases, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Zheng-Peng Li
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Song Guo
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China; Department of General Surgery, the 306th Hospital of Chinese PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Zheng-Yang Chen
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China; Department of General Surgery, the 306th Hospital of Chinese PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Bin-Bin Li
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Shao-Bin Chai
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Sheng-Yu Lu
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China; Department of General Surgery, the 306th Hospital of Chinese PLA-Peking University Teaching Hospital, Beijing 100101, China
| | - Hong-Feng Yan
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Pei-Ming Sun
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Tao Zhang
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Hong-Wei Sun
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Jian-Wu Yang
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Jin-Lian Zhou
- Department of Pathology, the Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China.
| | - He-Ming Yang
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China
| | - Yan Cui
- Department of General Surgery, Chinese PLA Strategic Support Force Characteristic Medical Center, Beijing 100101, China.
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28
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Pan K, Wang Y, Pan P, Xu G, Mo L, Cao L, Wu C, Shen X. The regulatory role of microRNA-mRNA co-expression in hepatitis B virus-associated acute liver failure. Ann Hepatol 2020; 18:883-892. [PMID: 31521462 DOI: 10.1016/j.aohep.2019.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 07/16/2019] [Accepted: 06/25/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Acute liver failure (ALF) is a dramatic disorder requiring intensive care. MicroRNAs (miRNAs) have been identified to play important roles in ALF. This study was performed to identify miRNA-mRNA co-expression network after ALF to investigate the molecule mechanism underlying the pathogenesis of ALF. MATERIALS AND METHODS The microarray dataset GSE62030 and GSE62029 were downloaded from Gene Expression Omnibus database. Overlapping differentially expressed miRNAs (DEmiRNAs) and genes (DEGs) were identified in liver tissues from patients with hepatitis B virus (HBV)-associated ALF in comparison with normal tissues from donors. Gene enrichment analysis was performed. Key pathways associated with the DEGs were identified. The miRNA-mRNA regulatory network was constructed. RESULTS Total 42 DEmiRNAs and 523 DEGs were identified in liver tissues from patients with HBV-associated ALF. Gene ontology and pathways enrichment analysis showed upregulated DEGs were related to immune responses, inflammation, and infection, and downregulated DEGs were associated with amino acids, secondary metabolites and xenobiotics metabolism. In miRNA-mRNA co-expression network, DEGs were regulated by at least one DEmiRNA and transcription factor. Further analysis showed DEmiRNAs, including has-miR-55-5p, has-miR-193b-5p, has-miR-200b-3p, and has-miR-3175 were associated with amino acid metabolism, drug metabolism and detoxication, and signaling pathways including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/AKT, Ras, and Rap1. CONCLUSIONS These miRNA-mRNA pairs and changed profiles were associated with and might be responsible for the impairment of detoxification and metabolism induced by HBV-associated ALF.
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Affiliation(s)
- Kanda Pan
- Department of Intensive Care Unit (ICU), The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
| | - Yunchao Wang
- Department of Intensive Care Unit (ICU), The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
| | - Ping Pan
- Department of General Medicine, The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
| | - Guanhua Xu
- Department of Intensive Care Unit (ICU), The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
| | - Lujiao Mo
- Department of Intensive Care Unit (ICU), The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
| | - Lijia Cao
- Department of Intensive Care Unit (ICU), The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
| | - Channi Wu
- Department of Gastroenterology, Zhejiang Xiaoshan Hospital, Xiaoshan District, Hangzhou, China.
| | - Xiaoyuan Shen
- Department of Intensive Care Unit (ICU), The First People's Hospital of Xiaoshan District, Hangzhou, Xiaoshan District, Hangzhou, China
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MiR-126 Regulates Properties of SOX9 + Liver Progenitor Cells during Liver Repair by Targeting Hoxb6. Stem Cell Reports 2020; 15:706-720. [PMID: 32763157 PMCID: PMC7486193 DOI: 10.1016/j.stemcr.2020.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 02/07/2023] Open
Abstract
Liver progenitor cells (LPCs) have a remarkable contribution to the hepatocytes and ductal cells when normal hepatocyte proliferation is severely impaired. As a biomarker for LPCs, Sry-box 9 (Sox9) plays critical roles in liver homeostasis and repair in response to injury. However, the regulation mechanism of Sox9 in liver physiological and pathological state remains unknown. In this study, we found that miR-126 positively regulated the expression of Sox9, the proliferation and differentiation of SOX9+ LPCs by suppressing the translation of homeobox b6 (Hoxb6). As a transcription factor, HOXB6 directly binds to the promoter of Sox9 to inhibit Sox9 expression, resulting in the destruction of the properties of SOX9+ LPCs in CCl4-induced liver injury. These findings revealed the role of miR-126 in regulating SOX9+ LPCs fate by targeting Hoxb6 in liver injury repair. Our findings suggest the potential role of miR-126 as a nucleic acid therapy drug target for liver failure.
miR-126 promotes Sox9 expression and maintains SOX9+ LPCs in adult mouse livers HOXB6 suppresses properties of SOX9+ LPCs in chronic liver injury model HOXB6 negatively regulates Sox9 trans-activity miR-126 regulates properties of SOX9+ LPCs by targeting Hoxb6
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Krauskopf J, Gosink MM, Schomaker S, Caiment F, Warner R, Johnson K, Kleinjans J, Aubrecht J. The MicroRNA-based Liquid Biopsy Improves Early Assessment of Lethal Acetaminophen Poisoning: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e919289. [PMID: 32086430 PMCID: PMC7049075 DOI: 10.12659/ajcr.919289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/24/2020] [Accepted: 11/04/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction of the outcome of the acetaminophen overdose are needed. Recently, using next-generation sequencing analysis of serum from human study participants we uncovered injury-specific signatures of circulating microRNAs (miRNAs) that represented underlying molecular mechanisms of toxicity. This case study is first to show the application of miRNA profiling to assess prognosis of acetaminophen poisoning. CASE REPORT The patient was admitted to the hospital following supra therapeutic acetaminophen ingestion. The patient showed elevated levels of biomarkers of hepatocellular injury alanine aminotransferase, aspartate transaminase, and glutamate dehydrogenase. Even though treatment with N-acetyl cysteine was initiated 24 hours post-ingestion, levels of alanine-aminotransferase and aspartate transaminase peaked at about 40 hours post ingestion of acetaminophen. We analyzed global circulating miRNA levels from 24 consecutive serum samples from this study participant covering the period from admission to time of death. CONCLUSIONS The resulting global miRNA profiles were compared with profiles from study participants with non-lethal acetaminophen poisoning and healthy controls. At the admission, the miRNA profiles of both lethal and non-lethal acetaminophen poisoning showed induction of cellular stress and oxidative damage. Later, the miRNA profiles of the lethal poisoning featured fibrosis and coagulation pathways while profiles of non-lethal cases resembled those of healthy study participants. Although additional confirmatory studies are needed, our case study is first to indicate that global miRNA profiles to be used as liquid biopsies have potential to facilitate the assessment of acetaminophen poisoning.
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Affiliation(s)
- Julian Krauskopf
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Mark M. Gosink
- Department of Pathology, University of Michigan, Ann Arbor, MI, U.S.A
| | - Shelli Schomaker
- Drug Safety Research and Development, Pfizer, Inc., Groton, CT, U.S.A
| | - Florian Caiment
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Roscoe Warner
- Department of Pathology, University of Michigan, Ann Arbor, MI, U.S.A
| | - Kent Johnson
- Department of Pathology, University of Michigan, Ann Arbor, MI, U.S.A
| | - Jos Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Jiri Aubrecht
- Drug Safety Research and Development, Pfizer, Inc., Groton, CT, U.S.A
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Hoffmann K, Nagel AJ, Tanabe K, Fuchs J, Dehlke K, Ghamarnejad O, Lemekhova A, Mehrabi A. Markers of liver regeneration-the role of growth factors and cytokines: a systematic review. BMC Surg 2020; 20:31. [PMID: 32050952 PMCID: PMC7017496 DOI: 10.1186/s12893-019-0664-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.
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Affiliation(s)
- Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany.
| | - Alexander Johannes Nagel
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Kazukata Tanabe
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | | | - Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Anastasia Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
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Kojima H, Nakamura K, Kupiec-Weglinski JW. Therapeutic targets for liver regeneration after acute severe injury: a preclinical overview. Expert Opin Ther Targets 2020; 24:13-24. [PMID: 31906729 DOI: 10.1080/14728222.2020.1712361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Liver transplantation is the only viable treatment with a proven survival benefit for acute liver failure (ALF). Donor organ shortage is, however, a major hurdle; hence, alternative approaches that enable liver regeneration and target acute severe hepatocellular damage are necessary.Areas covered: This article sheds light on therapeutic targets for liver regeneration and considers their therapeutic potential. ALF following extensive hepatocyte damage and small-for-size syndrome (SFSS) are illuminated for the reader while the molecular mechanisms of liver regeneration are assessed in accordance with relevant therapeutic strategies. Furthermore, liver background parameters and predictive biomarkers that might associate with liver regeneration are reviewed.Expert opinion: There are established and novel experimental strategies for liver regeneration to prevent ALF resulting from SFSS. Granulocyte-colony stimulating factor (G-CSF) is a promising agent targeting liver regeneration after acute severe injury. Autophagy and hepatocyte senescence represent attractive new targets for liver regeneration in acute severe hepatic injury. Liver support strategies, including tissue engineering, constitute novel regenerative means; the success of this is dependent on stem cell research advances. However, there is no firm clinical evidence that these supportive strategies may alleviate hepatocellular damage until liver transplantation becomes available or successful self-liver regeneration occurs.
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Affiliation(s)
- Hidenobu Kojima
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kojiro Nakamura
- Department of Surgery, Kyoto University, Kyoto, Japan.,Department of Surgery, Nishi-Kobe Medical Center, Kobe, Japan
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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Zan T, Piao L, Yang X, Gu Y, Liu B. Downregulation of microRNA-124 prevents the development of acute liver failure through the upregulation of PIM-3. Exp Physiol 2019; 105:108-119. [PMID: 31628693 DOI: 10.1113/ep087963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 10/17/2019] [Indexed: 12/16/2022]
Abstract
NEW FINDINGS • What is the central question of this study? Does miR-124 affect cell proliferation and apoptosis in acute liver failure (ALF) mice? • What is the main finding and its importance? Inhibiting miR-124 targets PIM-3 and thus upregulates its expression, consequently inhibiting liver cell apoptosis and promoting cell proliferation, ultimately preventing the progression of ALF. This highlights a promising competitive new target for ALF treatment. ABSTRACT Acute liver failure (ALF) is a complicated syndrome frequently leading to dysfunction and failure of various organs. MicroRNAs (miRNAs) have played crucial roles in the development and progression of human diseases, including ALF. However, the potential role of miR-124 in ALF still remains elusive. Thus, we investigated the underlying mechanism by which miR-124 influences ALF in a mouse model of ALF. Initially, ALF mouse models were established using d-galactosamine and lipopolysaccharide. Then we detected the serum biochemical parameters of liver, and pathological characteristics and ultrastructure of liver tissues. Next, we determined miR-124 and PIM-3 expression in liver tissues and cells using RT-qPCR and western blot analysis. The interaction between miR-124 and PIM-3 was identified using the dual luciferase reporter gene assay. Subsequently, expression of miR-124 and PIM-3 in liver cells was altered to explore their effects on primary liver cell proliferation, the cell cycle and apoptosis. The results obtained showed that ALF mice exhibited a decreased cholinesterase level with increased levels of alanine aminotransferase, aspartate transaminase and total bilirubin as well as abundant liver cell apoptosis and necrosis. miR-124 was upregulated while PIM-3 was downregulated in ALF tissues and cells. Besides, the PIM-3 gene was a target of miR-124 and was inhibited by miR-124. Overexpression of miR-124 or silencing of PIM-3 reduced Bcl-2 expression but elevated tumour necrosis factor α expression, and resulted in a reduction in liver cell proliferation but an increase in cell apoptosis in ALF mice. Altogether, miR-124 functions as a disease-promoting miRNA with potential in stimulating ALF by targeting PIM-3.
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Affiliation(s)
- Tao Zan
- Department of Intensive Care Unit, the First Hospital of Jilin University, Changchun, 130021, P.R. China
| | - Li Piao
- Department of Gynecology, the First Hospital of Jilin University, Changchun, 130021, P.R. China
| | - Xueqin Yang
- Department of Traditional Chinese Medicine, the First Hospital of Jilin University, Changchun, 130021, P.R. China
| | - Yue Gu
- Department of Hepatopancreatobiliary Surgery, the First Hospital of Jilin University, Changchun, 130021, P.R. China
| | - Baohua Liu
- Department of Emergency, the First Hospital of Jilin University, Changchun, 130021, P.R. China
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Abstract
For many years, major differences in morphology, motility, and mechanical characteristics have been observed between transformed cancer and normal cells. In this review, we consider these differences as linked to different states of normal and transformed cells that involve distinct mechanosensing and motility pathways. There is a strong correlation between repeated tissue healing and/or inflammation and the probability of cancer, both of which involve growth in adult tissues. Many factors are likely needed to enable growth, including the loss of rigidity sensing, but recent evidence indicates that microRNAs have important roles in causing the depletion of growth-suppressing proteins. One microRNA, miR-21, is overexpressed in many different tissues during both healing and cancer. Normal cells can become transformed by the depletion of cytoskeletal proteins that results in the loss of mechanosensing, particularly rigidity sensing. Conversely, the transformed state can be reversed by the expression of cytoskeletal proteins-without direct alteration of hormone receptor levels. In this review, we consider the different stereotypical forms of motility and mechanosensory systems. A major difference between normal and transformed cells involves a sensitivity of transformed cells to mechanical perturbations. Thus, understanding the different mechanical characteristics of transformed cells may enable new approaches to treating wound healing and cancer.
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Affiliation(s)
- Michael Sheetz
- Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore 117411
- Molecular MechanoMedicine Program and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA;
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Valizadeh A, Majidinia M, Samadi-Kafil H, Yousefi M, Yousefi B. The roles of signaling pathways in liver repair and regeneration. J Cell Physiol 2019; 234:14966-14974. [PMID: 30770551 DOI: 10.1002/jcp.28336] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 12/23/2018] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
The liver has remarkable regeneration potency that restores liver mass and sustains body hemostasis. Liver regeneration through signaling pathways following resection or moderate damages are well studied. Various cell signaling, growth factors, cytokines, receptors, and cell types implicated in liver regeneration undergo controlled hypertrophy and proliferation. Some aspects of liver regeneration have been discovered and many investigations have been carried out to identify its mechanisms. However, for optimizing liver regeneration more should be understood about mechanisms that control the growth of hepatocytes and other liver cell types in adults. The current paper deals with the possible applicability of liver regeneration signaling pathways as a target for therapeutic approaches and preventing various liver damages. Furthermore, the latest findings of spectrum-specific signaling pathway mechanisms that underlie liver regeneration are briefly described.
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Affiliation(s)
- Amir Valizadeh
- Stem Cells Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hossein Samadi-Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Cheng W, Liu G, Kong D, Huang W, Sun Y, Zhao D. Downregulation of miR‐1224 protects against oxidative stress‐induced acute liver injury by regulating hepatocyte growth factor. J Cell Biochem 2019; 120:12369-12375. [PMID: 30848506 DOI: 10.1002/jcb.28502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/12/2018] [Accepted: 12/13/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Wenting Cheng
- Department of Clinical Laboratory Nanjing Gaochun People's Hospital Nanjing Jiangsu China
| | - Guo‐pan Liu
- Department of Clinical Laboratory Nanjing Gaochun People's Hospital Nanjing Jiangsu China
| | - Dehua Kong
- Department of Clinical Laboratory Nanjing Gaochun People's Hospital Nanjing Jiangsu China
| | - Wei Huang
- Department of Clinical Laboratory Nanjing Gaochun People's Hospital Nanjing Jiangsu China
| | - Ying Sun
- Department of Clinical Laboratory Nanjing Gaochun People's Hospital Nanjing Jiangsu China
| | - Danmei Zhao
- Department of Clinical Laboratory Nanjing Gaochun People's Hospital Nanjing Jiangsu China
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Tao YC, Wang ML, Wang M, Ma YJ, Bai L, Feng P, Chen EQ, Tang H. Quantification of circulating miR-125b-5p predicts survival in chronic hepatitis B patients with acute-on-chronic liver failure. Dig Liver Dis 2019; 51:412-418. [PMID: 30274791 DOI: 10.1016/j.dld.2018.08.030] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 08/30/2018] [Accepted: 08/31/2018] [Indexed: 02/05/2023]
Abstract
AIMS To analyze the role of serum miR-125b-5p in reflecting liver damage and predicting outcomes in chronic hepatitis B (CHB) patients with acute-on-chronic liver failure (ACLF). METHODS CHB patients with normal hepatic function (n = 100), moderate-to-severe liver damage (n = 90), and ACLF (n = 136) were included. Among hepatitis B virus (HBV)-ACLF patients, 86 and 50 were in the training and validation cohorts, respectively. Serum miR-125b-5p level was measured by quantitative real-time PCR. RESULTS Serum miR-125b-5p level increased with disease progression, and serum miR-125b-5p level was lower in surviving than in dead HBV-ACLF patients. Among HBV-ACLF patients, miR-125b-5p positively correlated with total bilirubin (TBil; r = 0.214, p < 0.05) and model for end-stage liver disease (MELD) score (r = 0.382, p < 0.001) and negatively correlated with prothrombin activity(PTA; r = -0.215, p < 0.05). MiR-122 showed a contrasting performance compared with miR-125b-5p. Cox regression analysis showed that miR-125b-5p, miR-122, and PTA were independent survival predictors for HBV-ACLF, and low miR-125b-5p and high miR-122 levels may predict a longer survival in HBV-ACLF. MiR-125b-5p (AUC = 0.814) had a higher performance for survival prediction in HBV-ACLF compared with miR-122 (AUC = 0.804), PTA (AUC = 0.762), MELD score (AUC = 0.799), and TBil (AUC = 0.670) alone; predictive effectiveness of miR-125b-5p was increased by combination with miR-122 (AUC = 0.898). MiR-125b-5p was an effective predictor of HBV-ACLF outcomes in the validation cohort. CONCLUSIONS MiR-125b-5p increase is associated with severity of liver damage; high serum miR-125b-5p may serve as a predictor for poor outcomes in HBV-ACLF cases.
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Affiliation(s)
- Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China
| | - Ming Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China
| | - Yuan-Ji Ma
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China
| | - Ping Feng
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, PR China.
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Fathi-Kazerooni M, Kazemnejad S, Khanjani S, Saltanatpour Z, Tavoosidana G. Down-regulation of miR-122 after transplantation of mesenchymal stem cells in acute liver failure in mice model. Biologicals 2019; 58:64-72. [PMID: 30824230 DOI: 10.1016/j.biologicals.2019.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 11/28/2018] [Accepted: 02/19/2019] [Indexed: 01/13/2023] Open
Abstract
This study investigated the correlation between the hepatic level of miR-122 and the extent of liver tissue regeneration in CCl4 induced liver injury mice model following transplantation of menstrual blood-(MenSCs) and bone marrow-derived stem cells (BMSCs). Hepatic miR-122 levels were significantly up-regulated following administration of CCl4 (P < 0.01). The significant positive correlations were observed between hepatic miR-122 and biochemical serum markers and the severity of liver injury in histopathological assessments (P < 0.01). Following stem cell therapy, all cell treated groups showed a significant down-regulation in miR-122 that was significantly correlated with improvement in histopathological features and biochemical markers (P < 0.01). Furthermore, the hepatic level of miR-122 was lower in the MenSCs-treated group compared with the BMSCs-treated group (P < 0.01) and in HPL cells-treated groups in reference to undifferentiated cells-treated groups (P < 0.05). These data suggest that miR-122 could be used as a potential predictor of outcome of liver injury after mesenchymal stem cell transplantation.
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Affiliation(s)
- Mina Fathi-Kazerooni
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somaieh Kazemnejad
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Sayeh Khanjani
- Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Zohreh Saltanatpour
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Tavoosidana
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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39
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Miani M, Elvira B, Gurzov EN. Sweet Killing in Obesity and Diabetes: The Metabolic Role of the BH3-only Protein BIM. J Mol Biol 2018; 430:3041-3050. [DOI: 10.1016/j.jmb.2018.07.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/10/2018] [Accepted: 07/16/2018] [Indexed: 02/06/2023]
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40
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Wandrer F, Han B, Liebig S, Schlue J, Manns MP, Schulze-Osthoff K, Bantel H. Senescence mirrors the extent of liver fibrosis in chronic hepatitis C virus infection. Aliment Pharmacol Ther 2018; 48:270-280. [PMID: 29863282 DOI: 10.1111/apt.14802] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 12/27/2017] [Accepted: 04/24/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear. AIM To investigate the role of senescence and different senescence markers for fibrosis progression in patients with chronic hepatitis C virus (HCV) infection. METHODS The expression of the cell cycle inhibitors p21, p27 and p16 as well as the senescence markers p-HP1γ and γ-H2AX was analysed in liver tissue with different fibrosis stages. Senescence-associated chitotriosidase activity was measured in sera of HCV patients (n = 61) and age-matched healthy individuals (n = 22). RESULTS We found a remarkable up-regulation of the cell cycle inhibitors and senescence markers in chronic HCV infection compared to healthy liver tissue. Liver tissue with relevant fibrosis stages (F2-3) or cirrhosis (F4) revealed a significant increase in senescent cells compared to livers with no or minimal fibrosis (F0-1). In cirrhotic livers, a significantly higher number of p-HP1γ, p21 and p27 positive cells was detected compared to liver tissue with F2-3 fibrosis. Importantly, we identified T-cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, serum chitotriosidase was significantly elevated and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography. CONCLUSIONS Senescence of hepatic T-cells is enhanced in chronic viral hepatitis and increases with fibrosis progression. Serological detection of senescence-associated chitotriosidase might allow for the non-invasive detection of relevant fibrosis stages.
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Affiliation(s)
- F Wandrer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - B Han
- Leibniz Institute on Aging, Fritz Lipmann Institute, Jena, Germany
| | - S Liebig
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - J Schlue
- Department of Pathology, Hannover Medical School, Hannover, Germany
| | - M P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research (DZIF), Hannover, Germany
| | - K Schulze-Osthoff
- German Cancer Consortium (DKTK) and German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
| | - H Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Centre for Infection Research (DZIF), Hannover, Germany
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41
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Bantel H, Canbay A. Loss of KRAS control as consequence of downregulated microRNA-622 in hepatocellular carcinoma and its potential therapeutic implication. Gut 2018; 67:1206-1207. [PMID: 29353250 DOI: 10.1136/gutjnl-2017-315630] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 01/04/2018] [Accepted: 01/08/2018] [Indexed: 01/04/2023]
Affiliation(s)
- Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Ali Canbay
- Department for Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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Abstract
Liver regeneration after simple resection represents a unique process in which the organ returns to its original size and histologic structure. Over the past 30 years, there has been significant progress in elucidating the mechanisms associated with regeneration after loss of hepatic mass. Liver regeneration after acute liver failure shares several of these classical pathways. It differs, however, in key processes, including the role of both differentiated and stemlike cells. This article outlines these differences in addition to new molecular mechanisms, including immunomodulation, microRNAs, and the gut-liver axis. In addition, applications to the patient population, including prognostication and stem cell therapies, are explored.
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Affiliation(s)
- Keith M Wirth
- Department of Surgery, University of Minnesota Medical School, 420 Delaware Street SouthEast, MMC 195, Minneapolis, MN 55455, USA.
| | - Scott Kizy
- Department of Surgery, University of Minnesota Medical School, 420 Delaware Street SouthEast, MMC 195, Minneapolis, MN 55455, USA
| | - Clifford J Steer
- Departments of Medicine, and Genetics, Cell Biology and Development, University of Minnesota Medical School, 420 Delaware Street SouthEast, MMC 36, Minneapolis, MN 55455, USA
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Schueller F, Roy S, Vucur M, Trautwein C, Luedde T, Roderburg C. The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity. Int J Mol Sci 2018; 19:ijms19010261. [PMID: 29337905 PMCID: PMC5796207 DOI: 10.3390/ijms19010261] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/12/2018] [Accepted: 01/13/2018] [Indexed: 12/12/2022] Open
Abstract
Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed. MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets”. Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases. In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes. Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology. Here, we review the function of miRNAs in the context of acute and chronic liver diseases. Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine.
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Affiliation(s)
- Florian Schueller
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Sanchari Roy
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Mihael Vucur
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
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Roy S, Bantel H, Wandrer F, Schneider AT, Gautheron J, Vucur M, Tacke F, Trautwein C, Luedde T, Roderburg C. miR-1224 inhibits cell proliferation in acute liver failure by targeting the antiapoptotic gene Nfib. J Hepatol 2017. [PMID: 28645739 DOI: 10.1016/j.jhep.2017.06.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Patient outcome in acute liver failure (ALF) is crucially determined by the appropriate balance between cell death and compensatory cell proliferation. MicroRNAs (miRNAs) - small non-coding RNAs that function as guide molecules in RNA silencing - have evolved as crucial mediators of nearly all developmental and pathological processes, including the physiology and pathology of the liver. We investigated the role of miR-1224 during ALF. METHODS We measured miR-1224 in livers of mice in various acute liver disease murine models and in, patients with ALF, using quantitative real-time PCR. We studied the regulation of miR-1224 in AML12 cells and primary hepatocytes upon H2O2 stimulation. Cell proliferation and cell death were analysed by 5-bromo-2'-deoxyuridine and terminal deoxynucleotide transferase nick end labelling stainings, respectively. RESULTS We found that miR-1224 was up-regulated in hepatocytes upon ischaemia-reperfusion in vivo and in vitro. This was accompanied by impaired proliferation and elevated apoptosis. This function of miR-1224 was mediated by repressing the anti-apoptotic gene Nfib in hepatocytes. Strikingly, miR-1224 was also up-regulated in human livers and the serum of patients with ALF and indicated an unfavourable prognosis with an excellent prognostic value compared to other known serum markers in this clinical setting. CONCLUSIONS miR-1224 is a previously unrecognised regulator of proliferation after ALF in hepatocytes and represents a novel and specific biomarker of liver injury with prognostic value in ALF. Thus, miR-1224 may represent a target for novel therapeutic and diagnostic strategies in the context of ALF and warrants further testing as a biomarker in prospective trials. Lay summary: In acute liver failure, miR-1224 expression is modulated by oxidative stress. This leads to a decrease in hepatocyte cell proliferation and increase in apoptosis. Increased serum levels of miR-1224 could be a useful diagnostic marker in patients with acute liver failure.
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Affiliation(s)
- Sanchari Roy
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany
| | - Franziska Wandrer
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany
| | - Anne Theres Schneider
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany
| | - Jeremie Gautheron
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany
| | - Mihael Vucur
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany
| | - Tom Luedde
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
| | - Christoph Roderburg
- Department of Medicine III, University of Aachen (RWTH), Pauwelsstraße 30, 52074 Aachen, Germany.
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45
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Boyle M, Mann J. WITHDRAWN: Epigenetics in Chronic Liver Disease. J Hepatol 2017:S0168-8278(17)32255-9. [PMID: 28855099 DOI: 10.1016/j.jhep.2017.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 12/04/2022]
Abstract
This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.
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Affiliation(s)
- Marie Boyle
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK
| | - Jelena Mann
- Institute of Cellular Medicine, Faculty of Medical Sciences, 4(th) Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
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46
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Yu J, Zhang W, Qian H, Tang H, Lin W, Lu B. SOCS1 regulates hepatic regenerative response and provides prognostic makers for acute obstructive cholangitis. Sci Rep 2017; 7:9482. [PMID: 28842621 PMCID: PMC5573403 DOI: 10.1038/s41598-017-09865-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 07/31/2017] [Indexed: 12/31/2022] Open
Abstract
Acute obstructive cholangitis (AOC) is a common and severe infectious diseases that occurs in an obstructed biliary system. The suppressors of cytokine signaling (SOCS) family include well-known negative regulators of cytokine receptor signaling. However, few studies have been conducted to determine their function in AOC. In this study, we showed that SOCS1 expression aberrantly changed and was associated with AOC prognosis in rat models. Decreased SOCS1 expression enhances regenerative response after biliary drainage (BD) resulting from AOC by upregulating hepatocyte growth factor (HGF) signaling. To detect SOCS1 expression in the liver less invasively and to predict the prognosis for AOC after BD, miR-221 and miR-222 were investigated. Ectopic SOCS1 expression indirectly decreases miR-221/222 expression through Met in vitro. An inverse correlation between SOCS1 expression and miR-221/222 expression in liver tissue or in serum was verified in rats. Serum from AOC patients showed that lower expression of circulating miR-221/222 after endoscopic nasobiliary drainage was associated with delayed restoration of liver function. Our results showed that SOCS1 regulates hepatic regenerative response, and indirectly detecting downstream molecules, such as miR-221/222, may provide prognostic makers for AOC.
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Affiliation(s)
- Jianhua Yu
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Weiguang Zhang
- Department of Molecular Medicine and Clinical Laboratory, Shaoxing Second Hospital, Shaoxing, China
| | - Hongwei Qian
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Haijun Tang
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Weiguo Lin
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China
| | - Baochun Lu
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China.
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Abstract
BACKGROUND Dysregulation of miRNAs has been described in tissue and serum from patients with acute and chronic liver diseases. However, only little information on the role of miR-223 in the pathophysiology of acute liver failure (ALF) and liver cirrhosis is available. METHODS We analysed cell and tissue specific expression levels as well as serum concentrations of miR-223 in mouse models of acute (hepatic ischaemia and reperfusion, single CCl4 injection) and chronic (repetitive CCl4 injection, bile duct ligation (BDL)) liver diseases. Results were validated in patients and correlated with clinical data. The specific hepatic role of miR-223 was analysed by using miR-223-/- mice in these models. RESULTS miR-223 expression was significantly dysregulated in livers from mice after induction of acute liver injury and liver fibrosis as well as in liver samples from patients with ALF or liver cirrhosis. In acute and chronic models, hepatic miR-223 up-regulation was restricted to hepatocytes and correlated with degree of liver injury and hepatic cell death. Moreover, elevated miR-223 expression was reflected by significantly higher serum levels of miR-223 during acute liver injury. However, functional in vitro and in vivo experiments revealed no differences in the degree of liver cell death and liver fibrosis as miR-223-/- mice behaved identical with wild-type (wt) mice in all tested models. CONCLUSION miR-223 represents a promising diagnostic marker in a panel of serum markers of liver injury. Together with previously published data, our results highlight that the role of miR-223 in the pathophysiology of the liver is complex and needs further analysis.
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48
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Cho YE, Kim SH, Lee BH, Baek MC. Circulating Plasma and Exosomal microRNAs as Indicators of Drug-Induced Organ Injury in Rodent Models. Biomol Ther (Seoul) 2017; 25:367-373. [PMID: 28208010 PMCID: PMC5499614 DOI: 10.4062/biomolther.2016.174] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/04/2016] [Accepted: 12/13/2016] [Indexed: 12/12/2022] Open
Abstract
This study was performed to evaluate whether microRNAs (miRNAs) in circulating exosomes may serve as biomarkers of drug-induced liver, kidney, or muscle-injury. Quantitative PCR analyses were performed to measure the amounts of liver-specific miRNAs (miR-122, miR-192, and miR-155), kidney-specific miR-146a, or muscle-specific miR-206 in plasma and exosomes from mice treated with liver, kidney or muscle toxicants. The levels of liver-specific miRNAs in circulating plasma and exosomes were elevated in acetaminophen-induced liver injury and returned to basal levels by treatment with antioxidant N-acetyl-cysteine. Circulating miR-146a and miR-206 were increased in cisplatin-induced nephrotoxicity and bupivacaine-induced myotoxicity, respectively. Taken together, these results indicate that circulating plasma and exosomal miRNAs can be used as potential biomarkers specific for drug-induced liver, kidney or muscle injury.
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Affiliation(s)
- Young-Eun Cho
- Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.,Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892, USA
| | - Sang-Hyun Kim
- Department of Pharmacology, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Byung-Heon Lee
- Department of Biochemistry and Cell Biology, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Moon-Chang Baek
- Department of Molecular Medicine, CMRI, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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Chen Y, Xu J, Yang C, Zhang H, Wu F, Chen J, Li K, Wang H, Li Y, Li Y, Dai Z. Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity. Exp Mol Med 2017. [PMID: 28642576 PMCID: PMC5519018 DOI: 10.1038/emm.2017.80] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Long-term spaceflight affects numerous organ systems in the body, including metabolic dysfunction. Recently, ample evidence has demonstrated that the liver is a vulnerable organ during spaceflight. However, the changes in hepatocyte proliferation and cell cycle control under microgravity remain largely unexplored. In the present study, we first confirmed that the serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, biochemical markers of liver function, were altered in rats under tail suspension (TS) conditions to simulate microgravity, as shown in previous reports. Next, we demonstrated that the cell proliferation activity, determined by Ki67, PCNA and PH3, was significantly decreased at the different TS time points (TS for 14, 28 and 42 days) compared with that in the control group. Consistently, the positive cell cycle regulators Ccna2, Ccnd1, Cdk1, Cdk2 and cyclin D3 were also significantly decreased in the TS groups as shown by quantitative real-time PCR and western blotting analysis. Subsequent analysis revealed that the aberrant hepatocyte proliferation inhibition under simulated microgravity was associated with the upregulation of miR-223 in the liver. We further found that miR-223 inhibited the proliferation of Hepa1-6 cells and identified CDK2 and CUL1 as its direct targets. In addition, the decreased expression of CDK2 and CUL1 was negatively correlated with the level of p27 in vitro and in vivo, which may have been responsible for retarding hepatocyte proliferation. Collectively, these data indicate that upregulation of miR-223 was associated with the inhibition of liver cell growth and reveal the role of miR-223 in rat hepatocyte proliferation disorders and the pathophysiological process under simulated microgravity.
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Affiliation(s)
- Yongjie Chen
- School of Computer Science and Technology, Harbin Institute of Technology Shenzhen Graduate School, Shenzhen, Guangdong, China.,State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Ji Xu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Chao Yang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Hongyu Zhang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Feng Wu
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Jian Chen
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Kai Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Hailong Wang
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
| | - Yu Li
- School of Computer Science and Technology, Harbin Institute of Technology Shenzhen Graduate School, Shenzhen, Guangdong, China.,School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yinghui Li
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.,School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Zhongquan Dai
- State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
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50
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Loosen SH, Schueller F, Trautwein C, Roy S, Roderburg C. Role of circulating microRNAs in liver diseases. World J Hepatol 2017; 9:586-594. [PMID: 28515844 PMCID: PMC5411953 DOI: 10.4254/wjh.v9.i12.586] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/27/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small RNAs regulate gene expression by inhibiting the turnover of their target mRNAs. In the last years, it became apparent that miRNAs are released into the circulation and circulating miRNAs emerged as a new class of biomarkers for various diseases. In this review we summarize available data on the role of circulating miRNAs in the context of acute and chronic liver diseases including hepatocellular and cholangiocellular carcinoma. Data from animal models are compared to human data and current challenges in the field of miRNAs research are discussed.
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